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INTRODUCTION

Malaria affects about a quarter of a billion people and leads to almost 900,000 deaths annually. This disease is caused by infection with single-celled protozoan parasites of the genus Plasmodium. Five Plasmodium spp. are known to infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. P. falciparum and P. vivax cause most of the malarial infections worldwide. P. falciparum accounts for the majority of the burden of malaria in sub-Saharan Africa and is associated with the most severe disease. P. vivax accounts for half of the malaria burden in South and East Asia and >80% of the malarial infections in the America.

BIOLOGY OF MALARIAL INFECTION

Plasmodium sporozoites, which initiate infection in humans, are inoculated into the dermis and enter the bloodstream following the bite of a Plasmodium-infected female anopheline mosquito. Within minutes, sporozoites travel to the liver, where they infect hepatocytes via cell surface receptor-mediated events. This process initiates the asymptomatic prepatent period, or exoerythrocytic stage of infection, which typically lasts ~1 week.

During this period, the parasite undergoes asexual replication within hepatocytes, resulting in production of liver stage schizonts. When the infected hepatocytes rupture, tens of thousands of merozoites are released into the bloodstream and infect red blood cells. After the initial exoerythrocytic stage, P. falciparum and P.malariae are no longer found in the liver. P. vivax and P. ovale, however, can maintain a quiescent hepatocyte infection as a dormant form of the parasite known as the hypnozoite and can reinitiate symptomatic disease long after the initial symptoms of malaria are recognized and treated. Erythrocytic forms cannot reestablish infection of hepatocytes. Transmission of human-infecting malarial parasites is maintained in human populations by the persistence of hypnozoites (several months to few years for P. vivax and P. ovale), by antigenic variation in P. falciparum (probably months), and by the putative antigen variation in P. malariae (for as long as several decades).

The asexual erythrocytic stages of malarial parasites are responsible for the clinical manifestations of malaria. This part of the Plasmodium life cycle is initiated by merozoite recognition of red blood cells, mediated by cell surface receptors, followed by red blood cell invasion.

Once inside a red blood cell, the merozoite develops into a ring form, which becomes a trophozoite that matures into an asexually dividing blood stage schizont. Upon rupture of the infected erythrocyte, these schizonts release 8-32 merozoites that can establish new infections in nearby red blood cells. The erythrocytic replication cycle lasts for 24 h (for P. knowlesi), 48 h (for P. falciparum, P. vivax, and P. ovale), and 72 h (for P. malariae). Although most invading merozoites develop into schizonts, a small proportion become gametocytes, the form of the parasite that is infective to mosquitoes. Gametocytes are ingested into the mosquito midgut during an infectious blood meal and then transform ...